Multiple sclerosis (MS) is a chronic autoimmune disease caused by infiltration of peripheral immune cells into the central nervous system (CNS) through damaged blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB), which causes inflammation of the myelin sheaths around neuronal axons, and causes demyelination and scarring of the axons (McFarland and Martin (2007)). Almost any neurological symptom including physical and cognitive disability can appear with MS. The incidence of the disease is approximately 0.1% worldwide, and the disease onset usually occurs in young adults (more in females) (Benito-Leon (2011)). According to the National Multiple Sclerosis Society of United States, there are more than 70 FDA-approved medications for the treatment of MS, including Avonex (IFNβ-1a), Betaseron (IFNβ-1b), Gilenya (a sphingosine 1-phosphate receptor modulator), Glatiramer acetate (or Copolymer 1), and Tysabri (humanized anti-α-integrin antibody). However, these offer only palliative relief and are associated with serious adverse effects including increased infection, heart attack, stroke, progressive multifocal leukoencephalopathy, arrhythmia, pain, depression, fatigue, macula edema, and erectile dysfunction (Johnston and So (2012); Weber et al. (2012)).
Transplantation of mesenchynmal stromal/stem cells (MSCs) has emerged as a potentially attractive therapy due to their immunomodulatory and neuroregenerative effects (Auletta et al., (2012); Pittenger et al. (1999)) and potential ability to repair the blood-brain barrier (Chao et al. (2009); Menge et al. (2012)). MSCs are multipotent meaning they can generate a variety of cell lineages including adipocyte, chondrocyte, and osteoblast cells. They can be derived from fetal, neonatal, and adult tissues such as the amniotic membrane, umbilical cord, bone marrow, and adipose. MSCs have several unique advantages over current pharmacotherapies, as these cells can serve as carriers of multiple and potentially synergistic therapeutic factors, and can migrate to injured tissues to exert local effects through secretion of mediators and cell-cell contact (Uccelli and Prockop (2010a)). Importantly, MSCs have been found efficacious in the treatment of mice with experimental autoimmune encephalomyelitis (EAE), a well-recognized animal model of MS (Gordon et al., 2008a; Gordon et al. (2010); Morando et al. (2012); Peron et al. (2012); Zappia et al. (2005); Zhang et al. (2005)), as well as MS patients in clinical trials (Connick et al. (2012); Karussis et al. (2010); Mohyeddin Bonab et al. (2007); Yamout et al. (2010)). Xenogencity does not appear problematic as both mouse and human bone marrow-derived MSC (BM-MSC) can attenuate disease progression of EAE mice (Gordon et al. (2008a); Gordon et al. (2010); Morando et al. (2012); Peron et al. (2012); Zappia et al. (2005); Zhang et al. (2005)).
However, pitfalls exist for translating these findings from animals to patients. First, the limited sources and varying quality of human bone marrow (or other adult tissues) from different donors restrict the study and application of the MSCs, and prevent the standardization of the MSCs as a therapeutic product for large-scale clinical use. Second, these adult tissue-derived MSCs are highly mixed populations of cells, and perhaps only a portion of the cells exerts immunosuppressive effect. To obtain enough cells that are clinical grade for clinical use, one has to expand the MSC in vitro, which can decrease their immunosuppressive and homing abilities (Javazon et al. (2004)). Third, there are safety concerns about BM-MSC for possible malignant transformation of the cells (Wong (2011)), and potential transmission of pathogens from donors. Finally, varying effects were reported on EAE mice treated with BM-MSC in different reports (Gordon et al. (2008a); Payne et al. (2012); Zappia et al. (2005); Zhang et al. (2005)). Thus, the efficacy of BM-MSC on treatment of the disease is questionable.
Thus, there is a need for new therapies for the treatment of multiple sclerosis and other autoimmune diseases. There is also a need for an unlimited, safe, highly stable, efficient and consistent source of MSC to use as a treatment and prophylactic for these diseases as well as others.
It has been reported that human embryonic stem cells (hESC) can differentiate into embryoid bodies (EB), and then into a pool of cells with hemangioblast (HB) activities, i.e., they can further differentiate into vascular smooth muscle cells, endothelial cells, and hematopoietic cells (Chyou et al. (2008); Lu et al. (2007); Lu et al. (2009)). Therefore it was reasoned that a portion of these HB-containing cells could differentiate into MSCs, thus, eliminating the problems found with bone marrow-derived MSCs. These mesenchymal stem cells derived from human embryonic stem cell would be an unlimited, safe, and consistent supply of stem cells to be used to treat and prevent autoimmune diseases. Also disclosed herein are microarray analysis and other analysis, where several key factors are identified which differentially expressed in hES-MSC compared to BM-MSC.